Belatacept Post Depletional Repopulation to Facilitate Tolerance

This study will be a single-center, open-label,proof of concept study in non-human leukocyte antigen (HLA)-identical living and deceased donor renal transplants. The initial 20 subjects were randomized to either receive/not to receive a single donor bone marrow infusion in addition to the investigational combination of alemtuzumab, belatacept, and sirolimus. Since the bone marrow infusion has been eliminated in the second group of 20 subjects, no randomization was required. All recipients in the second group of 20 subjects will receive the same investigational combination of alemtuzumab, belatacept, and sirolimus.

At the time of transplant, participants will receive a 3-hour IV infusion of 30 mg. of alemtuzumab. Participants will receive a combination of sirolimus and belatacept for at least one year. At that time, eligible participants will consent to and begin oral immunosuppressive withdrawal or continue therapy through study close. Sirolimus will first be weaned by halving the dose and/or increasing the dosing interval over at least a 2-6 month period. After sirolimus is discontinued, participants will remain on monthly IV belatacept monotherapy indefinitely.

Follow-up will continue for at least five years. If subjects are successfully weaned from oral immunosuppression during their participation in this trial, no other alternative therapy will be warranted. Since belatacept is now FDA approved, subjects will be eligible to continue this therapy after their study participation has ended.

Inclusion criteria

• Recipients age 18 or older of an HLA-non-identical, living or deceased donor kidney transplant.
• A willing renal donor who consents for subsequent donation of donor blood for testing throughout the follow-up period and for use of his/her kidney in this experimental study.

Exclusion criteria

• Immunosuppressive drug therapy within 1 year prior to enrollment.
• Active malignancy or history of malignancy within 5 years of enrollment.
• Any history of blood malignancy or lymphoma.
• Any known immunodeficiency syndrome, including HIV infection.
• Absence of Epstein-Barr virus (EBV) or cytomegalovirus (CMV) specific antibodies in cases with evidence of EBV and/or CMV infection.
• Women of child-bearing potential unwilling or unable to use an acceptable method of birth control.
• Women who are pregnant or breastfeeding at the time of enrollment or study drug administration.
• Donor age <18 years.
• Subjects with protocol-specific etiologies of underlying renal disease.
• Subjects with a positive T-cell lymphocytic crossmatch or historical evidence of donor specific alloantibody by solid phase or flow-based detection methods.
• Prior solid organ transplant or potential to require a concurrent organ or cell transplant.
• Positive Hepatitis B or C antibodies and polymerase chain reaction (PCR) positive for the same.
• Active tuberculosis (TB) requiring treatment within the previous 3 years.
• Known positive purified protein derivative (PPD) unless chest x-ray is negative or treatment for latent TB has been completed.
• Active infection or other contraindications.
• History of drug or alcohol abuse within the past 5 years.
• Psychotic disorders which would interfere with adequate study follow-up.
• Active peptic ulcer disease, chronic diarrhea, or gastric malabsorption.
• All women 40 years or older with first degree family history of breast cancer will be required to have a screening mammogram within 6 months of study enrollment.
• Subjects with suspicion of breast malignancy which cannot be ruled out will be excluded.
• Belatacept use within 30 days prior to the day 1 visit.
• Prisoners or individuals who are involuntarily incarcerated.